Diabetes Mellitus complications.II
PATHOGENESIS OF THE DM
• Multifactorial, although persistent hyperglycemia
(“glucotoxicity”) seems to be a key mediator.
• Some tissue do not require insulin for glucose transport (e.g.,
nerves, lenses, kidneys, blood vessels),
• DM- widely affect different vascular structures:
• 1) Both large& Medium-sized muscular arteries (macrovascular
disease) - accelerated atherosclerosis (MI, infarction,CVA)
• 2) Capillary dysfunction in target organs (microvascular disease).
• The assessment of glycemic control is best measure by
glycosylated hemoglobin, also known as HbA1C, which is formed
by nonenzymatic covalent addition of glucose moieties to
hemoglobin in red cells.
• The American Dietetic Association recommends that HbA1C be
maintained below 7% in diabetic patients
PATHOGENESIS OF THE DM
• Hyperglycemia is not the only factor responsible for the
long-term complications of diabetes.
• The underlying abnormalities also play great role are:
• (1) Insulin resistance, (2) Co-morbidities e.g obesity.
• Three distinct metabolic pathways have been implicated
in the deleterious effects of persistent hyperglycemia on
peripheral tissues:
• I) Formation of Advanced Glycation End Products.
• II) Activation of Protein Kinase C.
• III) Intracellular Hyperglycemia and Disturbances in
Polyol Pathways.
PATHOGENESIS OF THE DM
• Three distinct metabolic pathways
• I) Formation of Advanced Glycation End Products-AGE.
• A) AGE-RAGE signaling axis: accelerates vessel injury&microangiopathy,
which is expressed on inflammatory reaction (endothelial SMA, macrophages
and T cells) - CK& GF \reactive oxygen species\procoagulant activit\
Proliferation of SM& synthesis of ECM.
• B) AGEs Cross-linking with(collagen type I in BV& type IV in BSM& Protein)
= Decreases their elasticity (Type I)+Increases extravasation of fluid (Type IV)
+ Decreases protein removal while enhancing protein& LDL deposition.
• II) Activation of Protein Kinase C (PCK): activation signal by
Ca[2]+ ions & 2nd messenger diacyl glycerol (DAG).
• Intracellular hyperglycemia stimulates>> synthesis of DAG from glycolytic
intermediates>> activation of PKC>>lead: Production of
(VEGF)=retinopathy+ Vasoconstrictor endothelin-1 ↓ levels NO “dilator”
+Profibrogenic factors like TGF-β , ↑ECM+ Production of PAI-1>
↓↓fibrinolysis>
vascular occlusive+ ↑↑ Pro-inflammatory factor (CK)
PATHOGENESIS OF THE DM
• Three distinct metabolic pathways
• III) Intracellular Hyperglycemia and Disturbances in
Polyol Pathways.(lense , kidneys , nerves, blood vessels)
• This excess glucose is metabolized by the enzyme Aldose reductase
to sorbitol, a polyol, &to fructose, uses NADPH-co-factor>>
Progressive ↓↓ NADPH by aldol reductase compromises GSH
regeneration, increasing cellular susceptibility to oxidative stress.
Morphology of DM& Its late complication.
The most important morphological changes in DM
are not related to pancreas (which is widely varies), but
to late systemic complication.
These are the major causes of morbidity and mortality.
Principal organs affected in diabetes mellitus :
Pancreas ( Islet Changes )
Diabetic Macrovascular Disease ( atherosclerosis)
Diabetic Microangiopathy (Small vessels )
Diabetic Nephropathy (Kidneys).
 Diabetic Ocular Complications (Retinopathy) eye
Diabetic Neuropathy (Nerves ).
1)Pancreas:
Surprisingly , pancreatic lesions are neither constant nor
necessarily pathognomonic.
They are more likely to be distinctive in typeI >> in typeII.
One or more of the following alterations may be present:
1. Reduction in the size and number of islets (DM-1) ↓islet
mass (DM-2).
2. Increase in the size and number of islet s (nondiabetic
newborns of diabetic mothers).
3. Beta cell degranulation.
4. Leukocytic infiltration (insulitis)- mostly T- cells,
Eosinophilic infiltrates (Autoimmune diseases)
5. Amyloid replacement of islets (DM-2)_ around capillaries &
b\w islet cells> obliteration & fibrosis.
6. Fibrosis of islet.
Insulitis- Type I DM
Amyloidosis- type II DM
Blood vessels. Small vessels (Diabetes microangiopathy) .
Diffuse thickening of basement membrane, more in the
capillaries of the skin , skeletal muscles, retina , renal
glomeruli , and renal medulla.
However, it may also be seen in such nonvascular structures
as renal tubules, Bowman’s capsule, peripheral nerves
and placenta.
Morphologic features:
Thickening appears as widening of the basement membrane
by a homogeneous , sometimes multilayered hyaline
substance , which is strongly positive with PAS stain.
Diabetic capillaries are more leaky than normal to plasma
proteins.
Diabetic Macrovascular Disease (Atherosclerosis).
1) Endothelial dysfunction- predisposes (LDL deposition)&
Myocardial diseases.
2) Accelerated atherosclerosis(large arteries: CVS, renal& CNS)
whatever their ages, within a few years of onset of type I&II.
3) Myocardial infarction, caused by AT of coronary arteries.
4) Gangrene of the lower extremities (vessels of lower extremities)
Hyaline arteriolosclerosis
• It is not specific for diabetes, a\w HTN.
• More severe in diabetics than in nondiabetics.
• It takes the form of an amorphous, hyaline thickening of the
wall of the arterioles, which causes narrowing of the lumen
Kidneys. (Diabetic Nephropathy ).
• The kidneys are second target for DM after the heart .
• The second leading cause of death after MI from DM.
• Three lesions are encountered:
• (1) Glomerular lesions: Capillary BM thickening by (EM), Tubular
BM thickening, Diffuse mesangial sclerosis with increase in
mesangial matrix > with time become nodule in configuration.
Nodular “intercapillary” glomerulosclerosis=Kimmelstiel-Wilson dis.
(ovoid or spherical, often laminated, nodules of mesangial matrix situated
in the periphery of the glomerulus+ Glomeruli arterioles show hyalnosis+
uninvolved lobules &glomeruli show striking diffuse mesangial sclerosis).
• (2) Renal vascular lesions, principally arteriolosclerosis of
•
diabetic patients (severe changes in the arteries& arterioles).
• (3) Pyelonephritis, including necrotizing papillitis:
•
Acute or chronic inflammation started in interstitium &
then spread to the tubules.+ Necrotizing papillitis=papillary necrosis.
Severe renal hyaline (afferent
art.) arteriolosclerosis
Nephrosclerosis long-standing DM
thickening of tubular BM
Nodular “intercapillary” glomerulosclerosis
Glomerular involvement
a-Diffuse glomerulosclerosis.
This consists of diffuse increase in mesagial matrix with
mild proliferation of mesangial
cells, and is always
associated with the overall thickening of the GBM. The
increase in mesangial volume appears to lag slightly
behind basement membrane widening
but becomes
pronounced after ten to 20 years of diabetes. The matrix
depositions are PAS positive. The changes almost always
begin in the vascular stalk
and sometimes seem
continuous with the invariably present hyaline thickening of
arterioles .As the diseases progresses, the mesangial
areas expand further and obliterate the mesangial cells
,gradually filling the entire glomerulus (obliterative diabetic
glomerulosclerosis).
b-Nodular glomerulosclerosis.
This is also known as intercapillary glomerulosclerosis of
Kimmelstiel -Wilson disease. The glomerular lesion
takes the form of ovoid or spherical , often laminated ,
hyaline masses situated in the periphery of the
glomerulus .The nodule are PAS positive and contains
lipids and fibrin .Often they contain trapped mesangial
cells.The nodular lesion is virtually pathognomonic of
diabetes.
c-Exudative lesions .(Fibrin cap. And capsular drop.).
The fibrin cap appears as homogeneous , brightly
eosinophilic, crescentic subendothelial deposit in a
peripheral capillary .The capsular drop is an eosinophilic ,
focal thickening of the parietal layer of bowman’s capsule ,
which apparently hangs into the uriniferous space . The
capsular drop is PAS positive and contains plasma
proteins.
2. Vessels involvement : Capillary basement membrane
thickening, widespread thickening of the glomerular capillary
basement membrane (GBM) occurs in virtually all diabetics,
irrespective of the presence of proteinuria ,and is part and
parcel of the diabetic microangiopathy . Pure capillary
basement membrane thickening can be detected only by
electron microscopy .Careful morphometric studies
demonstrate that this thickening begins as early as two years
after the onset of juvenile diabetes , and by five years
amounts to about a 30% increase80. the thickening continues
progressively , and usually concurrently with mesangial
widening . Simultaneously there is thickening of the tubular
basement membranes.
Renal atherosclerosis and arteriolosclerosis (hyaline)
3. Stroma :
The diabetes increase the
susceptibility to the
development of Pyelonephritis
and particularly papillary
necrosis (necrotizing papillitis)
Eyes. ( diabetic Retinopathy) .
Diabetes retinopathy classified in two groups :
Diabetes microangiopathy(non proliferative) may present as
(a) Thickening of the Basement membrane lead >>
(a-1) Breakdown of the blood-retinal barrier lead to
leakage with micro-occlusion >> giving rise to Macular
edema (VISUAL LOSS).
(b) Pericyte degeneration >>
(c) Microaneurysms >>>
(d) Retinal microhemorrhages
1) Intraretinal angiogenesis (proliferative phase) (of the disc or
elsewhere) known intraretinal microangiopathy=
(a) Retinal neovascularization (disrupted neovascular
membrane)>> Posterior vitreous detachment > Massive
vitreous hemorrhage.
(b) Organization >>
(c ) Retinal traction >> ( d) Retinal detachment >>
(e ) Visual distortion.
Eyes. ( Anterior chamber complications) .
1. CATARACT- lenticular opacities, opacification of the lens
nucleus (nuclear sclerosis).
2. Development of Neovacular membrane on iris surface
(a) Retinal neovascularization accompanied by >>
(b) Development of IRIS neovascular membrane >>
(c) Increased levels of VEGF in the aqueous humor.>>
3. Neovascular glaucoma:
(a) Contraction of the iris neovascular membrane >>
(b) Lead to adhesions >>>
(c) Occluding a major pathway for aqueous outflow>>
(d) Elevation of the intra-ocular pressure.
 Proliferative retinopathy.
This occurs in response to severe
ischemia and hypoxia of the retina.(
retinitis proliferans) .Is defined by the
appearance of new vessels on the
surface of either the optic nerve
head, which is termed
neovascularization of the disc, or the
surface of the retina
(neovascularization elsewhere)
Nerves ( Diabetic Neuropathy ).
•80% of DM> more than 15 years.
• Categorize as distal symmetric sensory or sensorimotor
neuropathy, autonomic neuropathy, and focal or multifocal
asymmetric neuropathy.
• The mechanism- is not completely resolved, but there is
evidence for involvement of both the polyol pathway and the
nonenzymatic glycation of proteins.
• Site: Peripheral nerves , brain, and spinal cord.
• morphologic features- most common
(a) Relative loss of small myelinated fibers and of unmyelinated
fibers, large fibers are also affected.(Diffuse or segmental)
(b) Endoneurial arterioles show thickening, hyalinization, and
intense periodic acid–Schiff positivity in their walls and
extensive reduplication of the basement membrane
THE END